Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Rapid CommunicationShort Communication

Simvastatin Hydroxy Acid Fails to Attain Sufficient Central Nervous System Tumor Exposure to Achieve a Cytotoxic Effect: Results of a Preclinical Cerebral Microdialysis Study

Yogesh T. Patel, Megan O. Jacus, Abigail D. Davis, Nidal Boulos, David C. Turner, Pradeep K. Vuppala, Burgess B. Freeman 3rd, Richard J. Gilbertson and Clinton F. Stewart
Drug Metabolism and Disposition April 2016, 44 (4) 591-594; DOI: https://doi.org/10.1124/dmd.115.068445
Yogesh T. Patel
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Yogesh T. Patel
Megan O. Jacus
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Abigail D. Davis
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nidal Boulos
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David C. Turner
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pradeep K. Vuppala
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Burgess B. Freeman 3rd
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard J. Gilbertson
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clinton F. Stewart
Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were potent hits against a mouse ependymoma cell line, but their effectiveness against central nervous system tumors will depend on their ability to cross the blood–brain barrier and attain a sufficient exposure at the tumor. Among 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that had activity in vitro, we prioritized simvastatin (SV) as the lead compound for preclinical pharmacokinetic studies based on its potential for central nervous system penetration as determined from in silico models. Furthermore, we performed systemic plasma disposition and cerebral microdialysis studies of SV (100 mg/kg, p.o.) in a murine model of ependymoma to characterize plasma and tumor extracellular fluid (tECF) pharmacokinetic properties. The murine dosage of SV (100 mg/kg, p.o.) was equivalent to the maximum tolerated dose in patients (7.5 mg/kg, p.o.) based on equivalent plasma exposure of simvastatin acid (SVA) between the two species. SV is rapidly metabolized in murine plasma with 15 times lower exposure compared with human plasma. SVA exposure in tECF was <33.8 ± 11.9 µg/l per hour, whereas the tumor to plasma partition coefficient of SVA was <0.084 ± 0.008. Compared with in vitro washout IC50 values, we did not achieve sufficient exposure of SVA in tECF to suggest tumor growth inhibition; therefore, SV was not carried forward in subsequent preclinical efficacy studies.

Footnotes

    • Received November 25, 2015.
    • Accepted January 21, 2016.
  • This research was supported by the Collaborative Ependymoma Research Network; the National Institutes of Health National Cancer Institute [Grant P30CA21765]; and the American Lebanese Syrian Associated Charities.

  • dx.doi.org/10.1124/dmd.115.068445.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Simvastatin Hydroxy Acid Fails to Attain Sufficient Central Nervous System Tumor Exposure to Achieve a Cytotoxic Effect: Results of a Preclinical Cerebral Microdialysis Study
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Rapid CommunicationShort Communication

Limited CNS Tumor Penetration of Simvastatin Hydroxy Acid

Yogesh T. Patel, Megan O. Jacus, Abigail D. Davis, Nidal Boulos, David C. Turner, Pradeep K. Vuppala, Burgess B. Freeman, Richard J. Gilbertson and Clinton F. Stewart
Drug Metabolism and Disposition April 1, 2016, 44 (4) 591-594; DOI: https://doi.org/10.1124/dmd.115.068445

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Rapid CommunicationShort Communication

Limited CNS Tumor Penetration of Simvastatin Hydroxy Acid

Yogesh T. Patel, Megan O. Jacus, Abigail D. Davis, Nidal Boulos, David C. Turner, Pradeep K. Vuppala, Burgess B. Freeman, Richard J. Gilbertson and Clinton F. Stewart
Drug Metabolism and Disposition April 1, 2016, 44 (4) 591-594; DOI: https://doi.org/10.1124/dmd.115.068445
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results and Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Preincubation Effects on Inhibition of OCT1 by CsA
  • Carbamazepine Metabolite and Hypersensitivity Reactions
  • SULT4A1 Preserves Mitochondrial Function
Show more Short Communication

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics